Impaired Inhibition by Avibactam and Resistance to the Ceftazidime-Avibactam Combination Due to the D179Y Substitution in the KPC-2 β-Lactamase

The ceftazidime-avibactam antibiotic combination was recently shown to be at risk for the emergence of resistance under treatment. To gain insight into the underlying mechanism, we have analyzed the catalytic properties of a Klebsiella pneumoniae carbapenemase type 2 (KPC-2) beta-lactamase harboring the (DY)-Y-179 substitution. We show that impaired inhibition by avibactam combined with significant residual activity for ceftazidime hydrolysis accounts for the resistance. In contrast, the (DY)-Y-179 substitution abolished the hydrolysis of aztreonam and imipenem, indicating that these drugs might provide therapeutic alternatives.